Identifying causal relationships between gastroesophageal reflux and extraesophageal diseases: A Mendelian randomization study
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ABSTRACT:
SUBMITTER: Yao P
PROVIDER: S-EPMC10869099 | biostudies-literature | 2024 Feb
REPOSITORIES: biostudies-literature
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Project description:The incidence of gastroesophageal reflux disease (GERD) is increasing with the advancement of world population aging, affecting the population health worldwide. Recently, there were several researches to suggest the association between GERD and sarcopenia, but evidence supporting the causal effect was absent. The purpose of this study is to determine the causal relationship between GERD and sarcopenia through a Mendelian randomization (MR) study. We conducted an MR analysis by using summary-level data of genome-wide association studies (GWASs) in the European population. The inverse variance weighted (IVW) method was used as the primary analytical method for evaluating causality. In addition, four other MR methods were performed to supplement the IVW results. We also used the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and the multivariable Mendelian randomization (MVMR) to validate the robustness of our results. IVW analysis revealed a causally positive correlation between low hand grip strength (OR = 1.2358, 95% C.I.: 1.0521-1.4514, P = 0.0099), decreased walking pace (OR = 0.1181, 95% C.I.: 0.0838-0.1666, P = 4×10-34), and decreased appendicular lean mass (ALM) (OR = 0.8612, 95% C.I.: 0.8263-0.8975, P = 1×10-12) and GERD. MR-PRESSO and MVMR analysis confirmed the association evidence. In conclusion, this MR analysis supported the causal association between sarcopenia-related traits and GERD.
| S-EPMC10968686 | biostudies-literature
Project description:BackgroundObservational epidemiological studies suggest that lung cancer risk may be raised by gastroesophageal reflux disease (GERD); however, the causal relationship between them remains unknown. Our study performed the two-sample Mendelian randomization (MR) approach to examine the causal relationship between GERD and lung cancer.MethodsInstrument variables were found to be independent single nucleotide polymorphisms (SNPs) that were highly linked with GERD (n = 129,080). Summary data from genome-wide association studies (GWAS) data were used to determine outcomes for lung cancer (n = 11,348), squamous cell lung cancer (LUSC), and lung adenocarcinoma (LUAD). In this study, three MR statistical techniques (inverse variance weighted (IVW), MR-Egger, and weighted median) were used to examine the potential causative relationship between GERD and the risk of lung cancer. Cochran's Q test, MR-Egger intercept test, leave-one-out analysis, and the funnel plot were all used in sensitivity analyses.ResultsThe main IVW method revealed that GERD substantially increased the risk of lung cancer [odds ratio (OR) = 1.37; 95% CI 1.16-1.63, p = 0. 0003], which was also supported by weighted median and MR-Egger analyses. Using IVW estimate, similar causal relationships were also observed between GERD and LUSC (OR = 1.56; 95% CI 1.26-1.93, p = 5.35 × 10-5 ) and LUAD (OR = 1.45; 95% CI 1.09-1.93, p = 0.01). Although potential heterogeneity was observed in some studies, random effect IVW was not violated by the heterogeneity, indicating that the causal effect was robust.ConclusionGERD was positively associated with the risk of lung cancer, for LUSC and LUAD. This study shed light on a new direction for prevent strategy of lung cancer and therapeutic perspectives in patients with GERD.
| S-EPMC10067102 | biostudies-literature
Project description:Background: Clinical observations and retrospective studies have observed that patients with gastroesophageal reflux disease (GERD) have an increased probability of dental erosion, periodontitis and oral mucosal lesions and other common oral lesions. However, whether there is a genetic causal relationship between GERD and the occurrence of oral lesions has not been reported. Methods: In this study, we extracted instrumental variables from the largest published summary statistics of the oral lesion phenotype GWAS in UK Biobank (UKBB) and GERD GWAS. Then, we performed a causal inference analysis between GERD and common oral lesions by mendelian randomization (MR) analysis with the R package "TwoSampleMR". Results: We observed a significant causal relationship between GERD and several common oral lesion phenotypes (painful gums, loose teeth, toothache, and mouth ulcers). GERD showed a positive correlation with the occurrence of these oral lesions. After removing outlier SNPs via the MR-PRESSO package, our conclusions were still robust. Conclusion: Our findings provide the first evidence for a genetic causal effect of GERD on oral lesion pathogenesis. For patients with confirmed GERD, attention should be paid to taking interventions to prevent the occurrence of oral lesions.
| S-EPMC9745088 | biostudies-literature
Project description:BackgroundThe incidence of gastroesophageal reflux disease (GERD) has been shown to be elevated in individuals with epilepsy. Traditional observational studies have led to a limited understanding of the effects of GERD and BE on epilepsy due to the interference of reverse causation and potential confounders.MethodsWe conducted a bidirectional two-sample Mendelian randomization (MR) analysis to determine whether GERD and BE can increase the risk of epilepsy. Genome-wide association study data on epilepsy and its subgroups were obtained from the International League Against Epilepsy consortium for primary analysis using three MR approaches and the FinnGen consortium for replication and meta-analysis. We calculated causal estimates between the two esophageal diseases and epilepsy using the inverse-variance weighted method. Sensitivity analysis was conducted to detect heterogeneity and pleiotropy.ResultsWe found a potential effect of genetically predicted GERD on the risk of epilepsy (odds ratio [OR] = 1.078; 95% confidence interval [CI], 1.014-1.146, p = .016). Specifically, GERD showed an effect on the risk of generalized epilepsy (OR = 1.163; 95% CI, 1.048-1.290, p = .004) but not focal epilepsy (OR = 1.059, 95% CI, 0.992-1.131, p = .084). Notably, BE did not show a significant causal relationship with the risks of generalized and focal epilepsy.ConclusionsUnder MR assumptions, our findings suggest a potential risk-increasing effect of GERD on epilepsy, especially generalized epilepsy. Considering the exploratory nature of our study, the association between GERD and epilepsy needs to be confirmed by future prospective studies.
| S-EPMC10498072 | biostudies-literature
Project description:Objectives: Correlations between obstructive sleep apnea (OSA) and gastroesophageal reflux disease (GERD) have been detected in previous observational studies. However, this association remains uncertain due to the potential presence of selection and confounding biases. Therefore, this bidirectional two-sample Mendelian randomization (MR) study was conducted to evaluate the causal relationship between OSA and GERD. Methods: In this study, instrumental variables (IVs) for OSA were selected from publicly available genetic summary data (27,207 cases and 280,720 controls). Summary statistics for GERD were obtained from a genome-wide association study of 602,604 individuals. The inverse variance weighted (IVW) method was used as the main MR method. The MR-Egger intercept test, MR pleiotropy residual sum and outlier, and leave-one-out analysis were used to detect pleiotropy. Heterogeneity was detected by Cochran's Q test. Results: The IVW results revealed that OSA [odds ratio (OR): 1.19, 95% confidence interval (CI): 1.11-1.28, p = 8.88E-07] was causally associated with the incidence of GERD. Moreover, there was evidence of GERD leading to OSA in the IVW analysis (OR: 1.44, 95%CI: 1.33-1.57, p = 7.74E-19). No directional pleiotropy was detected by the MR-Egger intercept test (all p > 0.05). Conclusion: This study found that OSA is linked to a higher incidence of GERD, and vice versa. This finding might be helpful for the screening and prevention of these two diseases.
| S-EPMC10113458 | biostudies-literature
Project description:BackgroundEmerging observational studies indicated an association between hyperthyroidism and gastrointestinal disorders. However, it remains unclear whether this association is causal, particularly in the case of gastroesophageal reflux (GERD) and esophageal cancer.MethodsTo assess the potential causal relationship between hyperthyroidism and GERD or esophageal cancer, we conducted a bidirectional 2-sample Mendelian randomization study. Independent genetic instruments for hyperthyroidism from the UK Biobank (N case=3,545 and N control=459,388) and public genome-wide association study (GWAS) dataset (N case=3,731 and N control=480,867) were used to investigate the association with esophageal cancer in the UK Biobank study (N case=740 and N control=372,016) and GERD in the public GWAS database (N case=20,381 and N control=464,217). Four different approaches (inverse variance weighted (IVW), weighted mode, MR-Egger, and weighted median regression) were used to ensure that our results more reliable. Additional sensitivity analyses were also performed to validate our results.ResultsWhen hyperthyroidism was considered as the exposure factor, it appeared to act as a protective factor for GERD (ORIVW = 0.88, 95% CI, 0.79-0.99, P = 0.039), while as a risk factor for esophageal cancer (ORIVW = 1.03, 95% CI, 1.01-1.06, P = 0.003). However, there is no evidence supporting a reverse causal relationship between genetic susceptibility to hyperthyroidism and GERD or esophageal cancer.ConclusionOur findings provided genetic evidence supporting bidirectional causal relationships between hyperthyroidism and GERD or esophageal cancer. These results substantiate certain discoveries from previous observational studies on a causal level and provide insight into relevant genetic susceptibility factors.
| S-EPMC11442246 | biostudies-literature
Project description:BackgroundPrevious observational studies have found an association between gastroesophageal reflux disease (GERD) and chronic respiratory diseases, but it remains uncertain whether GERD causally influences these diseases. In this study, we aimed to estimate the causal associations between GERD and 5 chronic respiratory diseases.Methods88 GERD-associated single nucleotide polymorphisms (SNPs) identified by the latest genome-wide association study were included as instrumental variables. Individual-level genetic summary data of participants were obtained from corresponding studies and the FinnGen consortium. We applied the inverse-variance weighted method to estimate the causality between genetically predicted GERD and 5 chronic respiratory diseases. Furthermore, the associations between GERD and common risk factors were investigated, and mediation analyses were conducted using multivariable MR. Various sensitivity analyses were also performed to verify the robustness of the findings.ResultsOur study demonstrated that genetically predicted GERD was causally associated with an increased risk of asthma (OR 1.39, 95%CI 1.25-1.56, P < 0.001), idiopathic pulmonary fibrosis (IPF) (OR 1.43, 95%CI 1.05-1.95, P = 0.022), chronic obstructive disease (COPD) (OR 1.64, 95%CI 1.41-1.93, P < 0.001), chronic bronchitis (OR 1.77, 95%CI 1.15-2.74, P = 0.009), while no correlation was observed for bronchiectasis (OR 0.93, 95%CI 0.68-1.27, P = 0.645). Additionally, GERD was associated with 12 common risk factors for chronic respiratory diseases. Nevertheless, no significant mediators were discovered.ConclusionsOur study suggested that GERD was a causal factor in the development of asthma, IPF, COPD and chronic bronchitis, indicating that GERD-associated micro-aspiration of gastric contents process might play a role in the development of pulmonary fibrosis in these diseases.
| S-EPMC10318641 | biostudies-literature
Project description:Observational studies have reported an association between gastroesophageal reflux disease (GERD) and endometriosis. We conducted a two-sample and bidirectional Mendelian randomization analysis to determine whether those associations are causal. Two-sample and bidirectional MR analyses were performed using summary statistics from the European Individual Genome-Wide Association Study (GWAS). The inverse variance weighting (IVW) method is used as the main analysis method to evaluate causality. Sensitivity analyses were performed to assess heterogeneity, horizontal versatility, and stability. The results showed no significant causal association between GERD in women with endometriosis in the UK Bank database [ratio (OR) ≈ 0, 95% adjusted interval (CI) 1.0007∼1.0044, P = 0.006] and Finn databases [ratio (OR) = 1.29, 95% adjusted interval (CI) 0.99∼1.67, P = 0.06]. However, when studying the Finn database only for endometriosis, which is confined to the uterus, a significant increase in GERD was limited to the risk of endometriosis in the uterus [ratio (OR) = 1.47, 95% adjusted interval (CI) 1.00∼2.17, P = 0.05]. Sensitivity analysis showed that the results were robust and did not detect multi efficacy or heterogeneity. Meanwhile, reverse MR analysis showed that endometriosis did not increase the risk of GERD. This MR study supports a causal relationship between GERD and an increased risk of endometriosis confined to the uterus. Therefore, patients with gastric esophageal reflux should be treated with gynecological examination to avoid and prevent the development of endometriosis.
| S-EPMC11558527 | biostudies-literature
Project description:BackgroundObservational studies have suggested a suspected association between gastroesophageal reflux disease (GERD) and respiratory diseases, but the causality remains equivocal. The goal of this study was to evaluate the causal role of GERD in respiratory diseases by employing Mendelian randomization (MR) studies.MethodsWe conducted Mendelian randomization analysis based on summary data of genome-wide association studies (GWASs) and three MR statistical techniques (inverse variance weighted, weighted median and MR-Egger) were employed to assess the probable causal relationship between GERD and the risk of respiratory diseases. Sensitivity analysis was also carried out to ensure more trustworthy results, which involves examining the heterogeneity, pleiotropy and leave-one-SNP-out method. We also identified 33 relevant genes and explored their distribution in 26 normal tissues.ResultsIn the analysis, for every unit increase in developing GERD, the odds ratio for developing COPD, bronchitis, pneumonia, lung cancer and pulmonary embolism rose by 72% (ORIVW = 1.72, 95% CI 1.50; 1.99), 19% (ORIVW = 1.19, 95% CI 1.11; 1.28), 16% (ORIVW = 1.16, 95% CI 1.07; 1.26), 0. 3% (ORIVW = 1.003, 95% CI 1.0012; 1.0043) and 33% (ORIVW = 1.33, 95% CI 1.12; 1.58), respectively, in comparison with non-GERD cases. In addition, neither heterogeneity nor pleiotropy was found in the study. This study also found that gene expression was higher in the central nervous system and brain tissue than in other normal tissues.ConclusionsThis study provided evidence that people who developed GERD had a higher risk of developing COPD, bronchitis, pneumonia, lung cancer and pulmonary embolism. Our research suggests physicians to give effective treatments for GERD on respiratory diseases. By exploring the gene expression, our study may also help to reveal the role played by the central nervous system and brain tissue in developing respiratory diseases caused by GERD.
| S-EPMC10790464 | biostudies-literature
Project description:Previous observational studies have investigated the relationship between obesity and the biliary tract and pancreas. The causality, however, is still to be confirmed. This study was designed to explore the causality between obesity which included body mass index(BMI), circumference (WC), hip circumference (HC) and waist-to-hip ratio (WHR), and pancreatobiliary diseases with a Two-Sample Mendelian Randomization(MR) analysis. single-nucleotide polymorphisms used in our study were derived from genome-wide association studies (GWAS). The inverse variance weighted was the dominated method to evaluate the causality. The heterogeneity was validated by Cochran's Q test. The pleiotropy was validated by MR-Egger regression and MR-PRESSO. The stability and reliability of the results were illustrated by the 'leave-one-out'sensitivity analysis. The MR results explored positive causal effects of BMI (OR: 1.021; 95% CI: from 1.016 to 1.027; P = 4.25 × 10-15) and WC (OR: 1.021; 95% CI: from 1.015 to 1.028; P = 1.65 × 10-10) on pancreatobiliary diseases. However, no causality existed between HC, WHR and pancreatobiliary diseases. This study reminded that general obesity and abdominal obesity required weight loss to prevent pancreatic biliary disease.
| S-EPMC10393843 | biostudies-literature